Method of making magnetically attractable particles

ABSTRACT

Magnetically attractable particles comprise a core of magnetic material encapsulated in a metal oxide coating. They may be made by emulsifying an aqueous solution or dispersion of the magnetic material or precursor, and an aqueous solution or sol of a coating inorganic oxide or precursor, in an inert water-immiscible liquid. The aqueous droplets are gelled, e,g. by ammonia or an amine., recoverd, and heated at 250°-2000° C. The resulting particles are generally smooth spheres below 100 microns in diameter and often of sub-micron size.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of applicants' copending U.S. Pat.application Ser. No. 355,651, filed May 22, 1989, and now abandoned.

This invention concerns a method of making magnetically attractableparticles, which are suitable for use in biological separations. Thereis an established market for such products.

BACKGROUND OF THE INVENTION

A variety of techniques have been developed for the production ofceramic particles which involve the precipitation of a precursor of thepowder from an aqueous solution containing the desired cations of theceramic. In many of these techniques, the solution is mixed with areagent which will precipitate the cations in the form of easilyreducible compounds, such as hydroxides, carbonates, oxalate, etc. Theprecipitates are separated from the liquid and sintered to reduce themto the respective oxides. A technique, which is particularlyadvantageous in developing ceramic particles in the micrometer size orless, is disclosed in co-pending Canadian patent application SerialNumber 544868-9, filed 19 Aug. 1987 of which one of the two inventors isalso co-inventor of this application.

Other techniques for preparing ceramic powders are disclosed in Frenchpatent 2,054,131. The patent disclosed the emulsification of an aqueoussolution of the metallic salts which form the ceramic. The emulsion istreated to remove the liquid and calcine the resultant solid phase toproduce the ceramic particles.

Considerable attention has also been given to the development of micronsize particles for use in biological treatments. A particular area ofinterest is the development of magnetic particles agglomerated orindividually coated with materials to which biological substances canadhere. Examples of magnetic particles for use in this manner aredisclosed in U.S. Pat. Nos. 3,330,693; 4,152,210 and 4,343,90l. EuropeanPatent application 176,638 published Apr. 9, 1986 also discloses the useof magnetic particles for the immobilization of biological protein.Several of these patents contemplate coating of the magnetic core with apolymeric material, or agglomerating several particles in a suitablepolymer such as disclosed in U.S. Pat. No. 4,343,90.

The use for magnetic materials in the biological field continues toincrease, hence an increased demand for superior materials. Consider,for example, the use of such particles for immobilizing enzymes orantibodies. Separation of such materials from other non-magnetic solidsby the use of a magnetic field permits separations and concentrationswhich would be otherwise difficult or even impossible to perform.Besides allowing separation of the support from suspended solids in theprocess liquids, the ease and power of magnetic collection permits theuse of very small support particles. In turn, this allows the use onnon-porous particles, while still retaining a reasonable specific areafor enzymes or antibodies. Another advantage of such magnetic materialsis their potential use in a magnetic stabilized fluid bed, therebypresenting further options in continuous reactor systems.

From the noted patents, a variety of magnetic materials have been usedin the preparation of magnetic supports matrices including iron, nickel,cobalt, and their oxides as well as composite materials such asferrites. However, such supports suffer from some disadvantages. First,metal ions from uncoated metal or metal oxide surfaces may irreversiblyinhibit some enzymes, particularly when the enzyme is attached directlyto the metal surface. Methods have been devised to attach the enzyme tothe inorganic material with the aid of intermediate crosslinking agentsand/or to coat the magnetic material with organic coatings as noted inU.S. Pat. No. 4,152,210.

Coating of magnetic material with inorganic coatings has also beenproposed. U.S. Pat. No. 4,343,901 describes a magnetic support matrixcomprising a porous refractory inorganic oxide, through the interior ofwhich are dispersed particles from about 0.05 micron to about 0.5millimeter of ferromagnetic materials, said oxide being impregnated witha polyamine cross-linked with an excess of a bi-functional reagent so asto furnish pendent functional groups. The refractory inorganic oxide,which may be obtained by a sol-gel technique, is calcined before use.Ferro-magnetic materials above 0.05 micron in size are notsuperparamagnetic and therefore exhibit permanent residual magnetism.Furthermore, the coatings proposed do not appear to be continuous and asa result would not prevent losses in enzyme activity.

Coated magnetic particles have been also devised for various alternativeuses. GB 2064502 describes a method of making coated magnetic particles,for use in ion-exchange resins, filter aids or absorbents, byprecipitating chromium hydrogel onto magnetic particles from 0.05 to 5microns in diameter and which are therefore not superpara-magnetic. Theproportion by weight of magnetic particles in the coated magneticparticles is at least 50%, generally 90 to 98%.

JP-A-6364308 describes magnetic fluids containing permanently suspendedparticles comprising ferromagnetic material dispersed in aheat-resistant inorganic oxide.

SUMMARY OF THE INVENTION

In one aspect this invention provides a method of making magneticallyattractable particles by the use of:

a) a precursor salt solution or sol or dispersion of magnetic material,

b) a precursor salt solution or sol of a coating inorganic oxide, and

c) an inert liquid immiscible with the solvent used in a) and b),

which method comprises emulsifying a) and b) either together orseparately in c), converting droplets of the emusion to a gel, andheating the resulting gel droplets to form magnetically attractableparticles comprising the magnetic material encapsulated in the coatinginorganic oxide.

In another aspect, the present invention provides water-dispersablemagnetically attractable particles comprising a mass of finely dividedsuperpara-magnetic material or "soft" magnetic material or low-Curiepoint magnetic material encapsulated in an inorganic oxide or hydratedoxide formed by a gel technique, the particles having the property ofbeing readily brought down out of dispersion by application of amagnetic field and of being readily re-dispersed after removal of themagnetic field.

In yet another aspect the invention provides a coated ferromagneticparticle having a diameter in the range of 0.1to 100 micrometers andcomprising a discrete core of magnetic material coated with a metaloxide selected from the group consisting of Al₂ O₃, SiO₂, TiO₂, ZrO₂,hydroxy-apatite and mixtures thereof, said coating weighing in the rangeof 1% to 95% of said core weight and providing a continuous coating overthe entire surface of said core to prevent exposure of said core tosurrounding media.

DETAILED DESCRIPTION OF THE INVENTION RECORD

Component a) is a precursor salt solution or dispersion of magneticmaterial. A precursor salt solution may be a mixture of salts inproportion chosen to give rise, on heating, to the desired magneticmaterial.

The magnetic material can be either one which would formsuperparamagnetic particles or one made of a soft magnetic material orone made of a low Curie point magnetic material. Superparamagnetism ischaracterized by the absence of any measurable permanent magnetization.Superparamagnetism is typically exhibited by magnetic particles withparticle size less than about 30 nm. Superparamagnetic materials areavailable commercially or may readily be made by known techniques. Softmagnetic materials are those that react quickly to changes in magneticfields and are characterized by a low permanent magnetization. Softmagnetic materials include a variety of so-called ferrites such asnickel zinc ferrite. Particles incorporating either superparamagnetic orsoft magnetic materials have the great advantage of being, not onlyreadily attractable out of dispersion by application of a magneticfield, but also readily re-dispersable when the magnetic field isremoved. Finally, particles with magnetic cores having low Curietemperatures can also be readily redispersed after exposure to magneticfields by heating above such a temperature at which permanentmagnetization is lost. There are many magnetic materials exhibiting lowCurie temperatures such as aluminum-substituted nickel ferrites, e.g.nickel ferro-aluminates NiFe_(2-2xo) Al_(2x) O₄ which may have Curietemperatures below 100° C. for ×=0.8.

Component b) can be formed of a variety of inorganic oxide or hydratedoxide materials, which may include Al₂ O₃, TiO₂, ZrO₂, Cr₂ O₃, Fe₂ O₃,CeO₂, In₂ O₃, Ga₂ O₃ SiO₂ or mixtures thereof or composites such ashydroxy-apatite. These are preferably derived from aqueous colloidaldispersions (sols) but may also be organic based, e.g. derived frommetal alkoxides. Colloidal sols can be developed in accordance with wellknown processing techniques. For example, a solution of the metal saltmay be neutralized with aqueous ammonia, aged and then peptized withnitric acid to a pH of approximately 2 to form colloids having aparticle size in the range of 10-50 nm. The starting colloidal oralkoxide sol may also contain various other components, for example,water soluble salts to tailor the composition and properties in themanner desired. Compositions may include, for example, biocompatibleglasses or hydroxy-apatites. Mixtures of sols can also be used in orderto give the required composite properties. Reactive species may also beincorporated, to provide surface sites for subsequent binding tocomponents, e.g. enzymes or substrates therefor, of biological systems.Surface active agents may be included to provide well-shaped gelparticles.

In another approach, a metal salt solution may be used in place of thesol.

These techniques permit a substantial degree of control over thechemistry of the resulting particles. For example, use of sols orsolutions based on ZrO₂ or TiO₂ was found to give rise to particleshaving excellent resistance to degradation and leaching of encapsulatedmaterial. Use of sols or solutions based on SiO₂ or Fe₂ O₃ was alsofound to give rise to particles that may have lower resistance todegradation and leaching, but which have numerous reactive sites forbinding to molecules of biological interest. Use of mixed sols andsolutions can give rise to particles having a desired combination ofresistance to degradation and leaching and biologically reactive sites.Incorporation of a powder passenger, e.g. of a refractory metal oxide,in the sol or solution may be useful in order to increase the specificsurface area of the particles and thus increase the number of sitesavailable for binding to molecules of biological interest. Particulatenon-magnetic refractory oxide material for this purpose may typicallyhave a particle size from 0.1 to 10 microns (but always less than thesize of the water-dispersable particles), and may typically be presentin a proportion of up to 40% by weight.

Component c) is an inert liquid immiscible in the solvents used in a)and b). This is used as the continuous phase of an emulsion and itsnature is not very critical. Suitable liquids include chlorinatedhydrocarbons such as i,i,i-trichloroethane, paraffin oil, andhydrocarbons such as hexane, heptane, octane and toluene. The art ofpreparing emulsions is well understood so that the selection of asuitable inert liquid is fully appreciated by those skilled in the art.

The first step of the method involves emulsifying components a) and b)in c). In one embodiment, finely divided magnetic material, in the formof a precipitate or aqueous dispersion, is dispersed throughout thesolution or sol b) and the resulting mixture is then emulsified in theimmiscible liquid c). In another embodiment, components a) and b) areseparately emulsified in component c), either at the same time or atdifferent times as described below.

The emulsion of particles is developed to produce droplets of chosensize which may be less than 100 micrometers and preferably less than 5micrometers. To promote the development of the emulsion, it ispreferable to include a suitable surfactant. Surfactants also lendstability to the emulsion once the desired droplet size has beendeveloped. Surfactants are often classified by the ratio of thehydrophilic-lipophilic balance (HLB) number. HLB numbers are determinedempirically and range from i to 40. Surfactants having HLB numbers; i.e.Less than 10 , are considered to be hydrophobic emulsifiers to formwater in oil emulsions. Hence for the preparation of the emulsion,suitable hydrophobic emulsifiers having HLB numbers Less than 10, suchas sorbitan monoleate or Span 80 (ICI, UK) are used.

The solutions, in this technique, can be made for example by usingdistilled water of the purity required to avoid introduction of unwantedcations, the wanted cations being introduced in the form of suitablewater soluble salts, e.g. nitrates, carbonates, acetates, etc. Thefraction of the solution can be theoretically as high as 74% by volumewhich corresponds to the theoretical maximum volume that can be occupiedby closely packed, uniform spherical particles. In practice, however, itis preferred to use a smaller fraction of about 30% to 50% by volume,since higher concentrations result in distortion from the sphericalshape of the dispersed phase leading to non-uniformity in size of theresultant coated particles.

The next step comprises treating the developed emulsion with a suitablereactant to gel the previously formed droplets. This is usually done bya change In pH. Such a change of pH should take place without breakingof the emulsion so that unformity and discreteness of the developeddroplets s maintained. Such change in pH can be accomplished by bubblingammonia through the emulsion or introducing ammonium hydroxide or aliquid amine, such as ethanolamine or hexamethylene diamine, into theemulsion. Other useful gases include CO₂ which may be bubbled throughthe solution.

The objective, however, of this aspect of the method is to coat theparticles developed in the above process steps. Depending upon when thecoating composition is introduced to the above steps, a variation inparticle size and shape can be achieved.

According to an aspect of the method, the colloidal particles of thecoating metal oxide may be added to the aqueous solution of salts of themetal ions of component a) prior to emulsification. In that case, thefinely dispersed solids added to the salt solution stabilize theemulsion and as a result, very fine particles of the order of 1micrometer can be obtained. This phenomenon of stabilization of emulsionby finely dispersed solids is well known. In this situation, the surfaceof the colloid can be modified by the controled absorption of somesurface active agents, such as sodium dodecyl sulfate, HLB greater than10, which make the particles hydrophobic and therefore preferentiallywettable by the oil phase.

The coating material b) can also be introduced at a later stage. In thatinstance, the coating material can be in the form of colloids suspendedin an aqueous solution or in the form of an aqueous solution containingthe respective cation or mixture of cations. Wetting of the emulsiondroplets by such coatings is preferred by rendering the droplet surfacehydrophilic. This is achieved by the addition of a surfactant having ahigh HLB value, for example, aliphatic polyethers, such as Antarox CO530TM having an HLB number of 10.8. or G1045 of HLB number of 11.5 orTween 80 of HLB number of 15 or also mixes of surfactants such as Tween80 or Span 80 adjusted in proportion to obtain a suitable HLB numberpreferably between 11 and 14. Dispersion of the emulsion droplets in thecoating solution is achieved by an emulsifier. Such an emulsificationproduces a multiple emulsion i.e. a water in oil in water emulsionusually noted as w/o/w/ emulsion. It was found that such a multipleemulsion was more stable and therefore that the coating was more uniformwhen (i) the emulsion droplets were washed by displacement washings withthe oil phase. Such washings were required to remove the excess amountof micelles created in the first emulsification step, and (ii) theamount of oil left with the emulsion droplets was minimum.

Coating thickness can be adjusted by re-emulsifying the dispersion toproduce a second emulsion using the previously noted Sorbitan monooleatesurfactant in the non-miscible solvent such as n-heptane.

According to another aspect of the process, after the coating materialis introduced in the form of a solution, the second emulsion may bereacted with a suitable reactant as previously indicated to precipitatethe coated ceramic particles.

In biological applications, it is apparent that with the minuteparticles it is essential that each particle be completely coated withan inert metal oxide to avoid contamination of the biological media withthe inner potentially toxic core which normally has some form ofmagnetic property.

The gel particles may be de-watered by conventional means and arethereafter recovered from the emulsion. The gel particles are heated, ifnecessary to convert to oxide or hydrated oxide. This may typicallyinvolve heating at 250 to 2000° C. The resulting particles are typicallyfrom 0.1 to 100 microns in diameter, and comprise magnetic materialencapsulated in a metal oxide coating, the weight ratio of magneticmaterial to coating being from 1.99 to 95:5. The particles may beirregular, but are often spherical. Different preparative processes giverise to particles having different characteristics:

Methods which involve first dispersing ferro-magnetic materials in anaqueous sol of a coating inorganic oxide. The particles typically have amagnetic material content below 50% e.g. from 1 to 40% by weight. Theyare typically spherical with an average size preferably from 0.5 to 10microns. They comprise a mass of finely divided magnetic materialencapsulated within the coating. It might have been supposed that themagnetic material would be uniformly distributed through the particlewith a significant proportion accessible to reagents at the surface.This is surprisingly found not to be the case. The ferro-magneticmaterial is substantially encapsulated with little or none, typicallyLess than 10%, of the material accessible at the surface. This is so,even when steps are deliberately taken to make the particles to someextent porous. It is an advantage that the ferromagnetic material is soreadily isolated from the biological processes occurring at theparticles.

Methods in which an aqueous solution of a precursor of the magneticmaterial is emulsified in the water-immiscible liquid. The particlescomprise a discrete core of magnetic material coated with a metal oxide,in which the coating typically weighs from 5 to 50% of the core. Newparticles generally have diameters in the range 5 microns and less,particularly in the range 0.1to 2 microns. These may have a somewhatirregular shape or a smooth spherical shape.

The magnetically attractable particles of this invention may be coupledto biological or organic molecules with affinity for or the ability toadsorb certain other biological or organic molecules. Particles socoupled may be used in a variety of in vitro or in vivo systemsinvolving separation steps or directed movement of coupled molecules tospecific sites. Application include, but are not limited toimmunological assays, other biological assays, biochemical or enzymaticreactions, affinity chromatography, cell sorting and diagnostic andtherapeutic uses.

These particles can be used as supports for immobilized enzymes,antibodies, antigens and other bioactive materials. The currentpractice, for example, In the industrial production of lactose-free milkis to add the enzyme β-galactosidase to milk in a conventional stir bankreactor and then allow a specific reaction to take place. Following thisthe milk is pasteurized which destroys the enzyme in the process. On theother hand if the enzyme were immobilized on a magnetic particle, suchas provided by this invention, it could be recovered by a magneticseparation and reused. The process of this invention is capable ofproducing coated particles having cores of a ferrite composition whichhave little or no tendency to retain a residual magnetism. Hence anyre-use would not result in particle aggregation which is associated withferrous materials due to retained magnetic properties of theferromagnetic composition. The use of these magnetic particles in such aprocess significantly improves the economics of the process.

Other considerations include new therapies which have been developed forthe treatment of diseases, such as childhood leukemia. Currentexperimental treatments include the use of magnetite, impregnatedpolystyrene beads which are coated with bioactivations. Biomaterialsspecifically recognize and bind to the surface of the leukemic cellsthus allowing the separation of diseased and healthy cells. The healthycells are reintroduced into the patient after all of his/her remainingbone marrow cells have been destroyed through aggressive chemotherapy.The problem with the existing technology is that the magnetic particlescurrently used in this type of therapy are quite large, that is, in therange of 5 micrometers or more. Unfortunately, smaller particles of thiscomposition are ineffective due to surface roughness. On the other hand,the coated ceramic particles of this invention are smooth and small forthis application, that is, in the range of 1 to 2 micrometers and willovercome the problems of the larger, rougher, magnetic impregnatedbeads.

The particles produced according to this invention, are also useful indiagnostic test. For example, in the examination of blood, there areusually several centrifugation steps involved to separate the variousfractions including cells, platelets, serum and plasma. If magneticparticles coated with the appropriate immobilized bioactive materialswere used, virtually all centrifugation steps could be eliminated whichopens the way for the development of rapid automated blood diagnosticequipment. This would considerably lower costs of the diagnosis andincrease the speed of testing.

The following Examples illustrate the invention.

EXAMPLE 1

49.5 g FeCl₂.4H₂ O and 202.4 g Fe(NO₃)₃ 9H₂ O were added to 250ml and50ml of distilled water respectively, and stirred until dissolved. Thesolutions were combined and added to 4.2 1 of aqueous NH₃ to precipitatethe hydrous Fe₃ O₄, which was washed with water to remove any salts. Theprogress of the washing was monitored by measuring the conductivity ofthe supernate and was considered to be complete when the conductivity <1mmhO. The precipitate was centrifuged yielding 86 g and was shown tocontain 25 w/o Fe₃ O₄ by gravimetric analysis.

73 g of the Fe₃ O₄ paste prepared above was dispersed into 54 ml 370gl⁻¹ ZrO₂ sol using a high shear mixer, 100 ml of distilled water wasrequired to reduce the viscosity to an acceptable level. 50 ml of thismixture was added to 150 ml of an immiscible organic solvent containinga surfactant (2.8 w/o Span 80/Genklene), and was dispersed to micronsized droplets using the high shear mixer. After 1 minute NH₃ gas wasused to gel the microspheres. The particles were then dewatered andcalcined at 400° C.

The obtained particles were subjected to magnetic fields ranging from+10000 Oe to -10000 Oe. The maximum extent of magnetization of theparticles was 37 e.m.u. per gram. A graph was drawn of magnetization(expressed as a proportion of the maximum possible) against appliedmagnetic field. The graph was a single line passing through the origin;no hysteresis loop was observed. This demonstrates that the particlesare superparamagnetic, and that they do not retain magnetization whenthe magnetic field is removed.

As predicted from the results in the previous paragraph, these particleswere readily brought down out of aqueous dispersion by application of amagnetic field and were readily re-dispersed after removal of themagnetic field.

Leaching tests carried out by mixing the particles for 14 hours in anaqueous medium buffered to pH3 and 11 showed iron concentrations of 720ppm and 0 ppm respectively (corresponding to the leaching of 4% and 0%of the iron contained in the magnetic core). Such concentrations aresignificantly Lower than those found from commercially availablemagnetic particles e.g. 4000 ppm and 3 ppm respectively.

EXAMPLE 2 Zirconia-coated magnetic particles.

By techniques described in example 1, particles containing 10%, 25%, 50%and 90% of Fe₃ O₄, were prepared. Scanning electron microscopes picturesof sections of the particles showed the following:

At 10% and 25% loading, the mass of finely divided Fe-₃ O₄ formed arather tight core, completely encapsulated in oxide, with no magneticmaterial detectable at the particle surface.

At 50% loading, the mass of finely divided Fe₃ O₄ formed a rather loosercore, but nevertheless with a surrounding layer of oxide, and little orno magnetic material being detectable at the particle surface.

At 90% loading, the mass of finely divided Fe₃ O₄ was concentratedtowards the centre of the particle, but an appreciable portion wasdetectable at the surface.

Pore size determination confirmed that, at 50% loading, the proportionof Fe₃ O₄ on the particle surface was negligible.

EXAMPLE 3

Mixed ZrO₂ /TiO₂ /Fe₃ O₄.

3g of ZrO₂ sol (oxide equivalent) prepared as per GB 1412937 (1975) washigher-shear mixed with 4g of a 0.4 micron nomina size TiO₂ powder(research powder from Tioxide Ltd.) for 5 minutes. 3g of a wet, hydratedFe₃ O₄ powder, prepared by conventional co-precipitation techniques wassubsequently added, and the mix high shear mixed for a further 5minutes. Total volume was 40 ml.

The mixture was added to 150ml of Genklene (1,1,1,-trichloroethane) / 1%sorbitan monooleate (Span 80) and the emulsion high shear mixed at 8500r.p.m. for 15 minutes. The spherical particles were subsequently gelledusing ammonia (NH₃) gas until complete gelation occurred. The particleswere dewatered and calcined at 400° C.

The product consisted of spheres of a mixed composition ZrO₂ /TiO₂ witha magnetic core. Typical size range was 2-3 microns with excellentsphere quality type, a narrow particle size distribution and goodmechanical strength.

EXAMPLE 4

Mixed TiO₂ /TiO₂ /Fe₃ O₄.

This was prepared as Example 3 using 3g TiO₂ sol, 4g TiO₂ 0.4 micronspassenger (Tioxide Ltd.) and 3g Fe₃ O₄. The mix was added to 150ml ofSpan/Genklene and was stirred at 300 r.p.m. for 15 minutes. Thespherical particles were subsequently gelled using NH₃ gas untilgelation was complete.

The product was a porous TiO₂ particle with a magnetic core. Typicalsize was around 50-60 microns with good sphere quality, narrow sizedistribution and good mechanical strength.

EXAMPLE 5

Mixed TiO₂ /TiO₂ /Fe₃ O₄.

This was performed as in example 4, but the Span/Genklene/powder mix washigh shear mixed at 8500 r.p.m. The product was a 2-3 micron particlewith good sphere quality, a narrow size distribution and good mechanicalstrength.

EXAMPLE 6

Mixed Fe₂ O₃ /Fe₃ O₄.

A slurry of 4.28g Fe₃ O₄ was added to 62.5 ml of a 2M solution ofFe(NO₃)₃. The mixture was homogenized and dispersed in 300 ml ofGenklene containing 5% Span 80. The dispersion was subjected to highshear for 5 minutes and then gelled by means of NH₃ gas. The particleswere separated from the supernatant liquid, washed with acetone, waterand ether, and fired at 400° C.

EXAMPLE 7

Alumina-Coated Magnetic Particles

A precursor salt solution was made up of ferric nitrate and lithiumnitrate in distilled water in a proportion that would result in lithiumferrite, LiFe₅ O₈, after drying and decomposition, the solutioncomprising 1010-g/L Fe (NO₃)₃.9H₂ O and 34.5 g/L LiNO₃. A sol ofcolloidal pseudoboehmite was prepared by techniques well known in theart of sol-gel techniques, peptized with nitric acid and treated withsodium dodecyl sulfate. This sol was transferred into the salt solutionin proportion that would result in a ratio Al₂ O₃ /LiFe₅ O₈ of 0.05.

The resulting sol solution was then emulsified in n-heptane, theemulsion consisting of 30% by volume of the aqueous solution, 70% byvolume of n-heptane and including 5% by volume of Span 80 as asurfactant and using a Brinkmann homogenizer as an emulsator. Ammoniagas was then bubbled through the emulsion until the pH had increased toabout 10 to 11. The water and heptane were removed by spray drying andthe resulting powder was calcined at 700° C. for 2 hours to result in anunagglomerated magnetic powder size distribution 0.1 to 0.5 micrometers.The TEM photomicrograph of the powder indicates that the particles arerelatively irregular in shape. The thickness of the alumina coating is,however, relatively uniform at 10 to 20 nanometers.

EXAMPLE 8

Zirconia-Coated Magnetic Particles

A precursor salt solution was made up nickel nitrate, zinc nitrate andferric chloride in distilled water in a proportion that would result innickel zinc ferrite, Ni₀.38 Zn₀.64 Fe₂ O₄, after drying anddecomposition. The solution was mixed with a sol of zirconium oxidesuspended in acetic acid solution obtained from Nyacol Product Inc. in aproportion that would result in a ratio ZrO₂ /Ni₀.38 Zn₀.64 Fe₂ O₄ of0.20.

The resulting sol solution was then emulsified, reacted with ammonia,dried and calcined as done in the previous example. Examination of thepowder under SEM indicate that the particles obtained are spheres ofdiameter varying between 0.5 to 0.8 micrometers.

Leaching tests carried out by mixing the particles in 1N nitric acidsolution for 24 hours indicate that the zirconia coating is veryeffective in protecting the magnetic core since no detectabledissolution of the iron could be measured.

EXAMPLE 9 Alumina-Coated Magnetic Particles

In Examples 7 and 8, the sol was added before emulsification of the saltsolution. In the present example, this procedure was modified as thealumina was added to the emulsified salt solution; the solutioncontaining zinc nitrate, nickel nitrate and ferric chloride wasemulsified in n-heptane, and treated with ammonia until the pH hadincreased to 10 to 11. The reacted-emulsion was diluted with freshheptane, mixed and settled and the supernatant heptane was then removed.Such a washing procedure was repeated 3 times. The emulsion was thendewatered using a "Dean Stark" dewatering trap. It was then washed asdescribed previously, settled for 1 day and the supernatant heptaneremoved. An alumina sol, similar to that of Example 11, in which 4% byvolume of Tween 80/Span 80 mix adjusted proportion to obtain a HLB valueof 13.0 had been added, was transferred into the emulsion In proportionthat would result in a ratio Al₂ O₃ /Ni₀.36 Zn₀.64 Fe₂ O₄ of 0.20. Themix was ultra-sonically dispersed and then emulsified again in n-heptanein the ratio by volume of 50%, using 2% by volume of Span 80 as thesurfactant. The water was subsequently removed by refluxing the emulsionin the dewatering trap. After the removal of the organic phase In thespray drier, the powder was calcined at 700° C. for 2 hours. Thecalcined powders that resulted had a particle size in the range lessthan 1 micrometer, were spherical with a core of magnetic lithiumferrite in an alumina shell.

Leaching tests showed that the amount of iron dissolved after 24 hoursimmersion in 1N nitric acid solutions was 0.55 ppm Fe₂ O₃. Such anamount corresponded to the dissolution of less than 0.1% of the totalFe₂ O₃ contained in the ferrite core.

The specific amount of proteins (i.e. prothromb bound on the particlesafter Immersion for a period of 15 minutes in a Tris HCI buffer solutionat pH of 7.4 was determined to be 0.57 μg per unit surface area of theparticles (cm²). Such an amount compares very favourably to thatobtained under the same experimental conditions for other supportsavailable on the market e.g. 0.47 μg/cm² for polystyrene surfaces and0.33 μg/cm² for PVC surfaces.

We claim:
 1. A method of making magnetically attractable particles bythe use of:a) a precursor salt solution or sol or dispersion of magneticmaterial, b) a precursor salt solution or sol of a coating inorganicoxide, and c) an inert liquid immiscible with an aqueous solvent used ina) and b), which method comprises emulsifying a) and b) either togetheror separately in c), converting droplets of the emulsion to a gel, andheating the resulting gel droplets to form magnetically attractableparticles comprising the magnetic material encapsulated in the coatinginorganic oxide.
 2. A method as claimed in claim 1, wherein the magneticmaterial of a) is dispersed throughout the solution or sol b) and theresulting mixture in then emulsified in c).
 3. A method as claimed inclaim 2, wherein a particulate non-magnetic refractory oxide is alsodispersed in the solution or sol b).
 4. A method as claimed in claim 1,wherein a solution of the magnetic material precursor a) is mixed withthe solution or sol b) and the resulting mixture is then emulsified inc).
 5. A method as claimed in claim 1, wherein a solution of themagnetic material precursor a) is emulsified in c) and the droplets ofthe emulsion converted to a gel, then the resulting gel droplets aredispersed in the solution or sol b), and the resulting mixture isemulsified In c), the droplets of the emulsion are converted to a gel,and the resulting gel droplets are heated to form the water dispersablemagnetically attractable particles.
 6. A method as claimed in claim 5,wherein the solution or sol b) containing the dispersed gel droplets isemulsified in c) in the presence of a surfactant having an HLB numbergreater than
 10. 7. A method as claimed in claim 1, wherein the magneticmaterial is superparamagnetic.
 8. A method as claimed in claim 1,wherein the magnetic material is a "soft" magnetic material.
 9. A methodas claimed in claim 1, wherein the magnetic material has a low Curietemperature.
 10. A method as claimed in claim 1, wherein ammonia or anamine is added to the emulsion to convert aqueous droplets thereof to agel.
 11. A method as claimed in claim 1, therein the gel droplets areheated at a temperature of 250-2000° C.